The present invention relates to processes for the preparation of 3,5-bis(trifluoromethyl)benzoic acid (CAS 725-89-3) which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The preparation of 3,5-bis(trifluoromethyl)benzoic acid from 3,5-bis(tiifluoromethyl)bromobenzene has been reported by Lichtenberger, J.; Weiss, F. Bull. Chem. Soc. Fr., 587, (1962). However, this reference quotes only a 49.5% yield of 3,5-bis(trifluoromethyl)benzoic acid from 3,5-bis(tifluoromethyl)bromobenzene.
The general processes disclosed in the art for the preparation of 3,5-bis(trifluoromethyl)benzoic acid result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of 3,5-bis(trifluoromethyl)benzoic acid in relatively high yield.
It will be appreciated that 3,5-bis(tiifluoromethyl)benzoic acid is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid via a very simple, short and highly efficient synthesis.
The novel process of this invention involves the synthesis of 3,5-bis(trifluoromethyl)benzoic acid. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula: 
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
The present invention is directed to processes for the preparation of 3,5-bis(trifluoromethyl)benzoic acid of the formula: 
A preferred embodiment of the general process for the preparation of 3,5-bis(trifluoromethyl)-benzoic acid is as follows: 
In accordance with the present invention, the treatment of the Grignard reagent from 3,5-bis(trifluoromethyl)bromobenzene with carbon dioxide gas at a temperature of less than about 0xc2x0 C. and preferably less than about xe2x88x9220xc2x0 C. provides 3,5-bis(trifluoromethyl)benzoic acid in higher yields than the processes disclosed in the art.
In a preferred embodiment, Grignard carboxylation of 3,5-bis-(trifluoromethyl)bromobenzene with Mg/CO2 in tetrahydrofuran, followed by crystallization of the product gives 3,5-bis(trifluoromethyl)benzoic acid.
In a preferred embodiment, the present invention is directed to a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid which comprises the reaction of 3,5-bis(trifluoromethyl)bromobenzene with magnesium in tetrahydrofuran to form a Grignard reagent followed by addition of the addition of carbon dioxide gas to the solution of the Grignard reagent in tetrahydrofuran and treatment with a strong acid to give 3,5-bis(trifluoromethyl)benzoic acid.
A specific embodiment of the present invention concerns a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid of the formula: 
which comprises:
treating 3,5-bis(trifluoromethyl)benzene of the formula: 
xe2x80x83with magnesium in an organic solvent to form the Grignard reagent of the formula: 
b) followed by treating the Grignard reagent with carbon dioxide gas in an organic solvent at an initial temperature of less than about 0xc2x0 C.,
c) followed by treatment of the product therefrom with a strong acid to give 3,5-bis(trifluoromethyl)benzoic acid of the formula: 
Preferred organic solvents for conducting the instant process include toluene, tetrahydrofuran (THF), diethyl ether, diglyme, methyl t-butyl ether. The more preferred organic solvent is tetrahydrofuran. In the formation of the Grignard reagent, tetrahydrofuran or diethyl ether are the more preferred organic solvents and tetrahydrofuran is the most preferred organic solvent.
The magnesium employed to prepare the Grignard reagent may be in the form of magnesium granules, magnesium turnings, magnesium dust, magnesium powder, suspension of magnesium in oil, and the like. To minimize safety risks, the use of magnesium granules is preferred.
In the present invention, it is preferred that the carbon dioxide be employed as carbon dioxide gas. It is more preferred that the carbon dioxide gas be at a pressure of 1 to 40 psi, it is still more preferred that the carbon dioxide gas be at a pressure of about 2 to 10 psi and it is even more preferred that the carbon dioxide gas be at a pressure of about 3 psi.
In the reaction of the Grignard reagent with carbon dioxide, it is preferred that the temperature upon addition of the carbon dioxide be less than about 0xc2x0 C. It is further preferred that the temperature of the reaction mixture upon addition of the carbon dioxide is less than about xe2x88x9210xc2x0 C. In the reaction of the Grignard reagent with carbon dioxide, it is more preferred that the temperature upon addition of the carbon dioxide be less than about xe2x88x9220xc2x0 C., it is even more preferred that the temperature upon addition of the carbon dioxide be less than about xe2x88x9240xc2x0 C., and it is still more preferred that the temperature upon addition of the carbon dioxide be less than about xe2x88x9245xc2x0 C.
In the present invention, it is preferred that the carbon dioxide be present in solution in the solvent at a concentration which provides optimal reaction with the Grignard reagent. The concentration of the carbon dioxide in the solvent may be enhanced by increasing the pressure of the carbon dioxide gas and/or decreasing the temperature of the solution.
Preferred strong acids for use in the instant process include hydrochloric acid, sulfuric acid, methanesulfonic acid, and the like. A more preferred strong acid for use in the present invention is hydrochloric acid.
Grignard formation from 3,5-bis(trifluoromethyl)bromobenzene under typical conditions using magnesium turnings (4 equiv.) labeled as xe2x80x9csuitable for Grignard reactionsxe2x80x9d, diethyl ether solvent, and slow addition of the starting bromide resulted in facile formation of Grignard adduct (1-2 hours).
The use of less than 2.1 eq of magnesium turnings resulted in incomplete consumption of bromide (residual bromide greater than 2-3 A%), while the use of more than 2.1 eq of magnesium turnings offered no advantage. A comparison of magnesium dust (freshly prepared), powder (50 mesh) and granules (20 mesh) showed that the Grignard reaction was complete for all within 1-2 hours at reflux in THF. The use of one type of magnesium over another (except for turnings) offered no advantage in terms of reaction profile, purity, or yield of the desired product. The use of magnesium granules is preferred, however, because magnesium granules present less of a safety hazard.
The Grignard formation is typically performed in tetrahydrofuran at reflux. The reaction is exothermic and the reaction may be controlled by the rate of addition of the bromide to the magnesium slurry. The reaction mixture is generally aged at reflux until  less than 1 mol % of bromide remains. Grignard formation is usually complete within 2 hours, however reaction times of up to 5 hours give comparable yields of 3,5-bis(trifluoromethyl)benzoic acid.
A solution of the Grignard reagent is then transferred to a pressure bottle where it is treated with a constant pressure of CO2. The carboxylation step was initially run at 20-25 psi for 3 hours at ambient temperature. In these preliminary investigations 3,5-bis(trifluoromethyl)benzoic acid was typically isolated acid in 76-78% yield (xe2x89xa798 wt %). At lower pressure (3 psi and ambient temperature), the assay yield of acid is less than those reactions run at 20-25 psi. The reaction profiles at 20-25 psi and 200 psi (ambient temperature) are essentially the same, thus higher pressure is generally unnecessary. At 20-25 psi, a moderate exotherm is observed upon introduction of the CO2(gas), as the reaction temperature increases from 0xc2x0 C. to 15xc2x0 C. over xcx9c3-4 minutes. At 200 psi the reaction exotherms from 0xc2x0 C. to 27xc2x0 C. instantaneously. A similar exotherm (xe2x88x9240xc2x0 C. to xe2x88x9225xc2x0 C.) is observed at xe2x88x9240xc2x0 C. addition of CO2(gas) at 20-25 psi. This suggests that exotherm control has minimal impact on reaction yield. The more important factor is the temperature of the reaction mixture as the CO2(gas) is first introduced. The carboxylation reaction is generally complete within one hour and the reaction profile remains essentially unchanged between one hour and 17 hours.
In accordance with the present invention, when the carboxylation was performed at xe2x88x9240xc2x0 C. the production of the proteo byproduct tris[3,5-bis(trifluoromethyl)benzene was minimized to 5% with a resulting 5% increase in carboxylation 3,5-bis(trifluoromethyl)benzoic acid. The proteo level rose back to the 10-11% level when the reaction is run at 0xc2x0 C. or xe2x88x9220xc2x0 C. Moreover, at xe2x88x9240xc2x0 C., the CO2 pressure could be decreased to 2 psi with no ill effects, presumably due to an increase in CO2 solubility at lower temperatures.
In the present invention, it is preferred that the CO2 be added to a solution of the Grignard in THF at xe2x88x9240xc2x0 C. When the Grignard was added to a CO2 saturated THF solution at xe2x88x9240xc2x0 C. an increase in the production of the proteo byproduct was observed. In addition, it is preferred that the pressure of CO2 be greater than atmospheric pressure. When the Grignard was prepared under a static atmosphere of CO2 (atmospheric pressure) significant byproduct formation was observed.
The acid is dissolved into aqueous base, and the neutral components are removed by extraction. 5% Aqueous NaOH, 5% aqueous Na2CO3 and 5% aqueous K2CO3 were evaluated as potential bases. 5% Na2CO3 was deemed the base of choice as this reagent did not lead to formation of as much of an emulsion as the other bases. Toluene, MTBE, EtOAc, and IPAc may be employed as wash solvents, however, EtOAc and IPAc are not preferred due to concerns over acetate hydrolysis, and MTBE and IPAc are not preferred due to high sodium salt solubility in these solvents. Toluene is the preferred extraction solvent. If, after quench and workup, the aqueous layer contains more than 2 mole % product, the aqueous layer may be backextracted with toluene to recover additional product.
In a preferred embodiment, the sodium salt is filtered through a bed of filter aid (such as solka floc) to ensure crystallization of the acid upon acidification. Attempted crystallization of the acid, without filtration of sodium salt, results in the acid oiling out of solution because the residue which is filtered off contains a small amount of dimer, some acid, and other unidentified byproducts. The oil may be converted to crystalline material by adding excess acid (conc. HCl) and aging overnight. Acid obtained by conversion of the oil is typically 80-90 wt %. By following a preferred embodiment of the present invention by utilizing filter aid filtration however, a 94% yield of material that is 99 wt % is typically isolated as a highly crystalline solid.
The 3,5-bis(trifluoromethyl)benzoic acid obtained in accordance with the present invention may be used as starting material in further reactions directly or following crystallization.
Many of the starting materials are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, normal phase or reverse phase chromatography.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.